Severe asthmatics remain poorly controlled despite standard asthma therapy and daily doses of high dose inhaled corticosteroids and/or systemic corticosteroids or their equivalent. They account for a large proportion of the morbidity and mortality associated with asthma. These patients are characterized by persistent symptoms and airway hyper responsiveness despite corticosteroid therapy. Mast cells are powerful, long-lived tissue dwelling effector cells that are resistant to corticosteroid effects and have been increasingly implicated in asthma pathobiology and the pathobiology of severe asthma. Imatinib is a specific tyrosine kinase inhibitor that inhibits cKit the receptor for stem cell factor (SCF) on mast cells. SCF is critical for mast cell homeostasis and function. Imatinib blocks mast cell mediator release and the development of airway responsiveness in a murine allergic model of asthma. Further, it has been shown to block the acute pulmonary inflammatory response in a mouse allergen challenge model. More importantly, in a chronic allergen challenge model, it blocks pulmonary tissue cellular infiltration and fibrosis. Imatinib has been used to treat CML and GIST tumors and is well tolerated even in non-oncologic trials. We therefore pose the following question: Can imatinib reduce lung mast cell numbers and function and improve outcomes in patients with severe, symptomatic asthma? We propose a double-blind, 6 month, placebo controlled, parallel group study of imatinib or placebo in patients with severe asthma and airway hyper responsiveness. In concert with our collaborating centers-through physiologic assessments, bronchoscopy with endobronchial biopsy/BAL, and multidetector CT imaging--we will characterize imatinib's effect on airway responsiveness, mast cell localization, phenotype, and function and airway wall thickness. We will also examine clinical outcomes and patient-reported outcomes. Analysis of predictors and indicators of subgroups of response will be examined. In an ancillary study, we will examine the contribution of circulating and bone-marrow derived mast cells to the mast cell population resident in the lung. RELEVANCE: Severe asthma, which may be associated with disordered function of specific inflammatory cells known as mast cells, accounts for a large proportion of the morbidity and mortality of asthma. We will study, whether imatinib, an inhibitor of mast cell number and function that is licensed for some types of cancers, but is well tolerated, improves the signs and symptoms of asthma while reducing the numbers and function of mast cells in the lung. This study will lay the groundwork for larger clinical studies using this drug, or others, to target mast cells in asthma. (End of Abstract)